Process for the manufacture of 2-keto-levo-gulonic acid and product thereof



PatentedMay 5, 1936 UNITED STATES PATENT OFFICE PROCESS FOR THE MANUFACTURE OF 2- -KETO-LEVO-GUIJONIC ACID AND UCT 'rrmnnor PROD- Tadeus Reichstein, Zurich, Switzerland, assignmto Hofimann-La Roche Inc., Nutley, N. 1., a corporation of New Jersey No Drawing.

Application February 6, 1935,

Serial No. 5,305. 'In Switzerland Mai-ch15,

6 Claims. (Gl.260-112) According to the process of U. Sf patent application Serial No. 748,925 2-keto-levo-gulonic acid is obtained by transforming levo-sorbose with the aid of carbonyl compounds, such as'formaldehyde,

acetone, methyl-ethyl-ketone, benzaldehyde, into bis-methylene-ether derivatives, treating these termediates thus obtained crystallize well, so that they may easily be purified.

Example 5 parts by weight of levo-sorbose, 40 parts by 1 weight of cyclo-hexanone and 2 parts by weight of concentrated sulphuric acid are shaken mechanically in a glass-stoppered bottle for 20 hours. The brown solution is diluted with ether and shaken with potash solution. After drying the solution is liberated from the ether and cycloe hexanone by distilling, and the residue is distilled in high vacuum. An almost colourless, thick oil is obtained which boils at 195-199 C. at 0.2

pressure; it solidifies to a glassy mass and when stirred with hot benzine it partially crys-' tallizes almost immediately. After suction and washing with benzine, the crystals represent the pure mono-cyclo-hexanone compound with a melting point of 161-162" C. The-di-cyclo-hexano'ne-sorbose is obtained from the benzine-solution. It crystallizes in fine needles melting at- 124" C. (corn) and is easily solublein the'cold in most'organic solvents except benzine and petroleum ether. Benzine and petroleuam/ether like-, wise dissolve the compound whe water the compound is almost insoluble. Its

specific rotation is [a]B=-23(c=2.07 in absolute methanol) heated. In-

' ately sets in. The product added. The reacpletely disappeared, then removed from the manganese dioxide by suction and washed with water. The filtrate is treated with carbonic acid and sulphuric acid until it is no longer alkalineto phenolphthaleine, but still alkaline to litmus paper, whereafter the product is dried in vacuo. The solid residue is freed from any di-cyclo-hexanoneether and hereafter the potassium salt of the acid is extracted by repeated boiling with absolute alcohol. On cooling the filtered alcoholic solution it crystallizes in needles, which are easily soluble in water, rather diflicultlyf soluble in absolute alcohol and insoluble in ether and benzene. By recrystallization from absolute alcohol thepotassium salt-may be obtained analytically pure. Its specific rotation is ]g= 15 ,69(c= 0.8 in water) 1.3 parts by weight of the salt are" dissolved in 4 parts by weight of water, 2 parts by weight of ice'areadded and thereafter a solution of 0.6 part by weight of concentrated sulphuric acid in 5 parts by weight of water and 1 part by weight of ice; The acid, which is im-. mediately precipitated, is removed by,suction, washed with ice water and dried in high vacuum. After recrystallization from benzene-benzine it isobtained as colourless leaflets melting at 132- 133 C. The di-cyclo-hexanone-2-keto-levogulonic acid forms colourless leaflets melting at 132-133 C.; it is easily soluble in ether, benzene and similar solvents, diflicultly soluble in benzine,

and the like. In water itis petroleum ether rather difllcultly 5 parts-by weight of di-cyclo-hexanone-Z-ketolevo-gulonic acid are boiled with parts by weight of water. The crystals first become pasty, then they are slowly then evaporated in vacuo. After seeding with 2- keto-levo-gulonic acid crystallization immedi- 4 thus obtained is identical with the 2-keto-levo-gulonic acid obtained according to the process of U. S. patent application Serial No. 748,925. a v I claim: 7 I

1. The process for the manufacture of 2-ketolevo-gulonic acid, which consists in transforming lfOVOrSOl'bOS? with the aid of alicyclic ketones containing a nuclear keto group into bis-methyleneether derivatives, treating these in alkaline solu- I tion with oxidizing agents which oxidize a CHaOI-I soluble. Its specific rotation is 'sorbose remaining unchanged by treatment with dissolved. The solution is. I

groupto 2 COOH group, and splitting oil the alicyclic ketones from the bis-methyIene-ether-Z- keto-levo-gulonic acid thus obtained by heating with water at an acid reaction.

cy'clo-hexanone from the iii-cyclo-hexanone-2- keto-levo-gulonic acid thus obtained by heating with water at-an acid reaction.

3. The process tor the manufacture of 2-ketolevo-gulonic acid, which consists in transforming levo-sorbose with the aid of cyclo-hexanone into aoaaosc' di-cyclo-henanone-levo-sorbose, treating the di-cycio-hexanone-ievo-sorbose in alkaline solution with potassium permanganate and-splitting oi! the cycio-hexanone from the di-cyclo-hexanone-.2-keto-levo-gulonic acid thus obtained by heating with water at an acid reaction.

4. 'As a new product a member of the group consisting of di-cyclo-hexanone 2 k'eto -1evo gulonic acid, and its salts.

5. As a new product, di-cyclo-hexanone-Z-ketolevo-gulonic acid.

6. As new products, the condensates of levov sorbose and an alicyclic ketone containing a nuclear keto group, said products having the ter-l minal primary alcohol group oxidized boxyl group. I

TADEUS REICHSTEIN.

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